| 1. |
- Caers, Jo, et al.
(author)
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Anti-Cd38 Single-Domain Antibodies in Disease Monitoring and Treatment
- 2023
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Patent (pop. science, debate, etc.)abstract
- NOVELTY - A pre-targeting system comprising an anti-cluster of differentiation (CD)38 single-domain antibody (sdAb) and a second agent capable of specifically binding to the anti-CD38 sdAb and comprising a second molecule is new, where the antibody comprises an amino acid sequence that comprises 3 complementary determining regions (CDR1-CDR3). The CDR1 is chosen from (a) an amino acid sequence of SEQ ID NO: 1, (b) polypeptides that have at least 80% amino acid sequence identity with SEQ ID NO: 1, and (c) polypeptides that have 3, 2 or 1 amino acid difference with SEQ ID NO: 1. The CDR2 is chosen from (a) an amino acid sequence of SEQ ID NO: 2, (b) polypeptides that have at least 80% amino acid sequence identity with SEQ ID NO: 2, (c) polypeptides that have 3, 2 or 1 amino acid difference with SEQ ID NO: 2.USE - The pre-targeting system is useful in kit of parts or medicine or diagnostics for diagnosing, monitoring and treating neoplastic disease in subject, and evaluating or monitoring presence, location and/or amount of CD38-expressing cells in subject. The neoplastic disease is a solid tumor. The neoplastic disease is hepatocellular carcinoma, lung cancer, melanoma, breast cancer or glioma, preferably hematological malignancy. The neoplastic disease is multiple myeloma, non-Hodgkin lymphoma (NHL) or chronic lymphoid leukemia (CLL), preferably multiple myeloma (all claimed).ADVANTAGE - The system exhibits excellent cytotoxic effect on CD38-expressing neoplastic cells.DETAILED DESCRIPTION - A pre-targeting system comprising an anti-cluster of differentiation (CD)38 single-domain antibody (sdAb) and a second agent capable of specifically binding to the anti-CD38 sdAb and comprising a second molecule is new, where the antibody comprises an amino acid sequence that comprises 3 complementary determining regions (CDR1-CDR3). The CDR1 is chosen from (a) an amino acid sequence of SEQ ID NO: 1, (b) polypeptides that have at least 80% amino acid sequence identity with SEQ ID NO: 1, and (c) polypeptides that have 3, 2 or 1 amino acid difference with SEQ ID NO: 1. The CDR2 is chosen from (a) an amino acid sequence of SEQ ID NO: 2, (b) polypeptides that have at least 80% amino acid sequence identity with SEQ ID NO: 2, (c) polypeptides that have 3, 2 or 1 amino acid difference with SEQ ID NO: 2. The CDR3 is chosen from (a) a 18 amino acid sequence (SEQ ID NO: 3) fully defined in the specification, (b) polypeptides that have at least 80% amino acid sequence identity with SEQ ID NO: 3, and (c) polypeptides that have 3, 2 or 1 amino acid difference with SEQ ID NO: 3. Tyr-Thr-Asp-Ser-Asp-Tyr-Ile (SEQ ID NO: 1), and Thr-Ile-Tyr-Ile-Gly-Gly-Thr-Tyr-Ile-His (SEQ ID NO: 2).INDEPENDENT CLAIMS are included for the following:kit of parts comprising the pre-targeting system;use of pre-targeting system or kit of parts in medicine or diagnostics for diagnosing, monitoring and treating a neoplastic disease in a subject; andimaging method for evaluating or monitoring presence, location and/or amount of CD38-expressing cells in a subject involves (i) detecting, in a subject to whom a detectable quantity of the pre-targeting system, and (ii) generating an image representative of the location and/or quantity or intensity of the signal, where the second agent comprises a signal-emitting molecule, has been administered, signal emitted by said signal-emitting molecule.
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| 2. |
- Caers, Jo, et al.
(author)
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Radiotheranostic Agents in Hematological Malignancies
- 2022
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In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Research review (peer-reviewed)abstract
- Radioimmunotherapy (RIT) is a cancer treatment that combines radiation therapy with tumor-directed monoclonal antibodies (Abs). Although RIT had been introduced for the treatment of CD20 positive non-Hodgkin lymphoma decades ago, it never found a broad clinical application. In recent years, researchers have developed theranostic agents based on Ab fragments or small Ab mimetics such as peptides, affibodies or single-chain Abs with improved tumor-targeting capacities. Theranostics combine diagnostic and therapeutic capabilities into a single pharmaceutical agent; this dual application can be easily achieved after conjugation to radionuclides. The past decade has seen a trend to increased specificity, fastened pharmacokinetics, and personalized medicine. In this review, we discuss the different strategies introduced for the noninvasive detection and treatment of hematological malignancies by radiopharmaceuticals. We also discuss the future applications of these radiotheranostic agents.
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| 3. |
- Dhulesia, Anne, et al.
(author)
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Local Cooperativity in an Amyloidogenic State of Human Lysozyme Observed at Atomic Resolution.
- 2010
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In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 132:44, s. 15580-15588
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Journal article (peer-reviewed)abstract
- The partial unfolding of human lysozyme underlies its conversion from the soluble state into amyloid fibrils observed in a fatal hereditary form of systemic amyloidosis. To understand the molecular origins of the disease, it is critical to characterize the structural and physicochemical properties of the amyloidogenic states of the protein. Here we provide a high-resolution view of the unfolding process at low pH for three different lysozyme variants, the wild-type protein and the mutants I56T and I59T, which show variable stabilities and propensities to aggregate in vitro. Using a range of biophysical techniques that includes differential scanning calorimetry and nuclear magnetic resonance spectroscopy, we demonstrate that thermal unfolding under amyloidogenic solution conditions involves a cooperative loss of native tertiary structure, followed by progressive unfolding of a compact, molten globule-like denatured state ensemble as the temperature is increased. The width of the temperature window over which the denatured ensemble progressively unfolds correlates with the relative amyloidogenicity and stability of these variants, and the region of lysozyme that unfolds first maps to that which forms the core of the amyloid fibrils formed under similar conditions. Together, these results present a coherent picture at atomic resolution of the initial events underlying amyloid formation by a globular protein.
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| 4. |
- Dumoulin, Mireille, et al.
(author)
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A camelid antibody fragment inhibits the formation of amyloid fibrils by human lysozyme.
- 2003
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 424:6950, s. 783-8
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Journal article (peer-reviewed)abstract
- Amyloid diseases are characterized by an aberrant assembly of a specific protein or protein fragment into fibrils and plaques that are deposited in various organs and tissues, often with serious pathological consequences. Non-neuropathic systemic amyloidosis is associated with single point mutations in the gene coding for human lysozyme. Here we report that a single-domain fragment of a camelid antibody raised against wild-type human lysozyme inhibits the in vitro aggregation of its amyloidogenic variant, D67H. Our structural studies reveal that the epitope includes neither the site of mutation nor most residues in the region of the protein structure that is destabilized by the mutation. Instead, the binding of the antibody fragment achieves its effect by restoring the structural cooperativity characteristic of the wild-type protein. This appears to occur at least in part through the transmission of long-range conformational effects to the interface between the two structural domains of the protein. Thus, reducing the ability of an amyloidogenic protein to form partly unfolded species can be an effective method of preventing its aggregation, suggesting approaches to the rational design of therapeutic agents directed against protein deposition diseases.
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| 5. |
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| 6. |
- Kumita, Janet R, et al.
(author)
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Disease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster
- 2012
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In: The FASEB Journal. - : Federation of American Society of Experimental Biology (FASEB). - 0892-6638 .- 1530-6860. ; 26:1, s. 192-202
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Journal article (peer-reviewed)abstract
- We have created a Drosophila model of lysozyme amyloidosis to investigate the in vivo behavior of disease-associated variants. To achieve this objective, wild-type (WT) protein and the amyloidogenic variants F57I and D67H were expressed in Drosophila melanogaster using the UAS-gal4 system and both the ubiquitous and retinal expression drivers Act5C-gal4 and gmr-gal4. The nontransgenic w(1118) Drosophila line was used as a control throughout. We utilized ELISA experiments to probe lysozyme protein levels, scanning electron microscopy for eye phenotype classification, and immunohistochemistry to detect the unfolded protein response (UPR) activation. We observed that expressing the destabilized F57I and D67H lysozymes triggers UPR activation, resulting in degradation of these variants, whereas the WT lysozyme is secreted into the fly hemolymph. Indeed, the level of WT was up to 17 times more abundant than the variant proteins. In addition, the F57I variant gave rise to a significant disruption of the eye development, and this correlated to pronounced UPR activation. These results support the concept that the onset of familial amyloid disease is linked to an inability of the UPR to degrade completely the amyloidogenic lysozymes prior to secretion, resulting in secretion of these destabilized variants, thereby leading to deposition and associated organ damage.-Kumita, J. R., Helmfors, L., Williams, J., Luheshi, L. M., Menzer, L., Dumoulin, M., Lomas, D. A., Crowther, D. C., Dobson, C. M., Brorsson, A.-C. Disease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster.
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